In fact, differential release of peptide and classic transmitters from the same cell has been demonstrated for several types of neurons and is probably a result of the differences in vesicle storage described earlier. Because of their proximity to the active zones, nonpeptide vesicles can be released rapidly (<1 msec) in response to single action potentials • BOX 6.1 Some Neuroactive Peptides as a result of localized influx of Ca++ . Thus, low-frequency stimulation of the cell causes just the release of nonpeptide transmitter. In contrast, with higher-frequency stimulation of the presynaptic neuron, there is a more global increase in [Ca++] throughout the nerve terminal that leads to release of neuropeptide as well as neurotransmitter.
When neuropeptides are co-released with other transmitters, they may act synergistically or antagonistically. For example, in the spinal cord, tachykinins and calcitonin gene–related peptide (CGRP) act synergistically with glutamate and with substance P to enhance the action of serotonin. Conversely, tachykinins and CGRP antagonize norepinephrine’s action at other synapses. The interactions, however, are not simply a one-to-one synergism or antagonism at a particular synapse because of the differing temporal and spatial profiles of the action of peptides versus classic transmitters. In particular, the slower release and lack of rapid reuptake mean that neuropeptides can act for long durations, diffuse over a region of brain tissue, and affect all cells in that region (that have the appropriate receptors) rather than just acting at the specific synapse at which it was released. In fact, studies have shown that there is often a spatial mismatch between the presynaptic terminals that contain a particular neuropeptide and the sites of the receptors for that peptide. In sum, peptides released from a particular synapse probably affect the local neuronal population as a whole, whereas the co-released classic transmitters act in more of a point-to-point manner.
Opiates are drugs derived from the juice of the opium poppy. Compounds that are not derived from the opium poppy but that exert direct effects by binding to opiate receptors are called opioids and form a clinically and functionally important class of neuropeptides. Operationally, opioids are defined as compounds whose effects are stereospecifically antagonized by a morphine derivative called naloxone.
The three major classes of endogenous opioid peptides in mammals are enkephalins, endorphins, and dynorphins. Enkephalins are the simplest opioids; they are pentapeptides. Dynorphins and endorphins are somewhat longer peptides that contain one or the other of the enkephalin sequences at their N-terminal ends.
Opioid peptides are widely distributed in neurons of the CNS and intrinsic neurons of the gastrointestinal tract. The endorphins are discretely localized in particular structures of the CNS, whereas the enkephalins and dynorphins are more widely distributed. Opioids inhibit neurons in the brain involved in the perception of pain. Indeed, opioid peptides are among the most potent analgesic (pain-relieving) compounds known, and opiates are used therapeutically as powerful analgesics. They exert their analgesic effect by binding to specific opiate receptors.
Substance P is a peptide consisting of 11 amino acids. It is present in specific neurons in the brain, in primary sensory neurons, and in plexus neurons in the wall of the gastrointestinal tract. The wall of the gastrointestinal tract is richly innervated with neurons that form networks or plexuses (see also ). The intrinsic plexuses of the gastrointestinal tract exert primary control over its motor and secretory activities. These enteric neurons contain many of the neuropeptides, including substance P, that are found in the brain and spinal column. Substance P is involved in pain transmission and has a powerful effect on smooth muscle.